Apoptosis

Apoptosis is the process of programmed cell death, the deliberate suicide of a cell in a multicellular organism for the greater good of the whole individual. In contrast to necrosis, which is a form of cell death that results from acute tissue injury, apoptosis is carried out in an ordered process that generally confers advantages during an organism's life cycle. For example, the differentiation of human fingers requires the cells in between the fingers to initiate apoptosis so that the fingers can separate. As will be explained further on, the way the apoptotic process is executed facilitates the safe disposal of cell corpses and fragments.

The fact that apoptosis has been the subject of increasing attention and research efforts was highlighted by the award of the 2002 Nobel Prize in Physiology or Medicine to Sydney Brenner (Great Britain), H. Robert Horvitz (US) and John E. Sulston (GB) "for their discoveries concerning genetic regulation of organ development and programmed cell death" (see [1] ).

Table of contents
1 Functions of apoptosis
2 Apoptotic process
3 Evolutionary origin of the apoptotic process

Functions of apoptosis

Cell damage or infection

Apoptosis can occur, for instance, when a cell is damaged beyond repair, or infected with a virus. The "decision" for apoptosis can come from the cell itself, from its surrounding tissue or from a call that is part of the immune system.

If a cell's capability of apoptosis is damaged (for example, by mutation), or if the initiation of apoptosis is blocked (by a virus), a damaged cell can continue dividing without restrictions, developing into cancer. For example, as part of the hijacking of the cell's genetic system carried out by human papiloma viruses (HPV), a gene called E6 is expressed in a product that degrades p53 protein, which is a vital piece of the apoptotic pathway. This severe interference in the apoptotic capability of cells plays a critical role in the fact that persistent infection by oncogenic HPVs can result in the development of cervical cancer (see "Integration of interferon-alpha/beta signaling to p53 responses in tumor suppression and antiviral defense", by Akinori Takaoka et al., Nature Vol. 424, number 6948, July 31, 2003, p. 517).

Response to stress or DNA damage

Stress conditions --such as starvation-- as well as damage to the cell's DNA --resulting from toxicity or exposure to ionizing radiation, such as ultraviolet or X-rays-- can induce a cell to begin an apoptotic process. A fascinating example, resulting from damage to the genome in the cell nucleus, is cell suicide triggered by the nuclear enzyme poli(ADP-ribose) polymerase-1, or PARP-1. This enzyme plays a crucial role in maintaining genomic integrity, and massive activation of PARP-1 can deplete the cell of energy-providing molecules, an event that sends signals from the nucleus for the mitochondrion to start the apoptotic process (see the Perspective "PARP-1 -a Perpetrator of Apoptotic Cell Death?", by Alberto Chiarugi and Michael A. Moskowitz, in Science, Vol. 297, No. 5579, p. 200, and the research report by Seong-Woon Yu, et al., in p. 259, in the same issue).

Immune cell regulation

Some cells of the immune systems, the
B cells and T cells, can become autoreactive, attacking healthy body cells. These are destroyed via apoptosis. New T cells are tested for autoimmune reactions within the thymus so that they do not attack healthy body cells right away. About 95% of the freshly produced T cells are killed right away via apoptosis due to autoimmune reactions.

Development

Programmed cell death is an integral part of metazoa (multicellular animals) tissue development, and it does not elicit the inflammatory response which is characteristic of necrosis (see "Mechanisms and Genes of Cellular Suicide", by Hermann Steller, Science Vol. 267, Mar. 10, 1995, p. 1445). In other words, apoptosis does not resemble the sort of reaction that comes as a result of tissue damage due to accident or pathogenic infection. Instead of swelling and bursting --and, hence, spilling their internal contents into extracellular space--, apoptotic cells and their nuclei shrink, and often fragment. In this way, they can be efficiently phagocytosed (and, as a consequence of this, their components reused) by macrophages or by neighboring cells.

Research on chick embryos -- specifically on chick neural tube development -- has suggested how selective cell proliferation, combined with selective apoptosys, sculpts developing tissues in vertebrates. During vertebrate embryo development, structures called the notocord and the floor plate secrete a gradient of the signaling molecule Sonic hedgehog (Shh), and it is this gradient that directs cells to form patterns in the embryonic neural tube: cells that receive Shh in a receptor in their membranes called Patched1 (Ptc1) survive and proliferate; but, in the absence of Shh, one of the ends of this same Ptc1 receptor (the carboxyl-terminal, inside the membrane) is cleaved by caspase-3, an action that exposes an aptotosys-producing domain. (See the Perspective "Longing for Ligand: Hedgehog, Patched, and Cell Death", by Isabel Guerrero and Ariel Ruiz i Altaba, in Science Vol. 301, No. 5634, p. 774; and the research report "Inhibition of Neuroepithelial Patched-Induced Apoptosis by Sonic Hedgehog" by Chantal Thibert, et al., in p. 843 of that same issue, Aug. 8, 2003).

Research like the one carried out by Thibert and her colleagues has begun to clarify some of the fundamental aspects of morphogenesis, or the development of organisms from fertilized eggs to fully-developed animals and plants. It has also suggested specific answers to why normal cells carry out apopotosis when they end up outside the places they should be in body tissues.

Homeostasis

In the adult organism, the number of cells within an organ or tissue has to be constant within a certain range. Blood and skin cells, for instance, are constantly renewed by their respective progenitor cells; but this proliferation has to be compensated by cell death. This is called homeostasis, although some authors and researchers like Steven Rose and Antonio Damasio have suggested homeodynamics as a more accurate and elocuent term (see Damasio: The Feeling of What Happens, Harcourt Brace & Co., New York, 1999, p. 141).

Homeostasis is achieved when the rate of mitosis (cell proliferation) in the tissue is balanced by cell death. If this equilibrium is disturbed, either of two things happen:

  • The cells are dividing faster than they die, effectively developing a tumor.
  • The cells are dividing slower than they die, which results in a disorder of cell loss.
Both states can be fatal or highly damaging. For instance, misregulation of Hedgehog (Hgg) protein signalling (see previous section, Development) has been implicated in several forms of cancer. Hgg, which conveys an anti-apoptotic signal, has been found to be overexpressed in pancreatic adenocarcinoma tissues (see "Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis" by Sarah P. Thayer et al., Nature Vol. 425, pgs. 851-856, Oct. 23, 2003).

Apoptotic process

Morphology

A cell undergoing apoptosis shows a characteristic morphology that can be seen under a microscope:
  1. The cell becomes round (circular). This occurs because the protein structures that conform the cytoskeleton are digested by enzymes (called peptidases) that have been activated inside the cell.
  2. Its nucleus and the DNA inside it undergo condensation.
  3. Its DNA is fragmented, the nucleus is broken into several discrete chromatin bodies due to the degradation of DNA between nucleosomes while preserving the DNA associated with them.
  4. The cell is phagocytosed, or,
  5. The cell breaks apart into several vesicles called apoptotic bodies\.

(See "Apoptosis in the Pathogenesis and Treatment of Desease", by Craig B. Thompson, in Science, Vol. 267, p. 1456, Mar. 10, 1995.)

Biochemical signals for safe disposal

The dying cells that have just been described display "eat me" signals, like phosphatidylserine (PS, a phospholipid from the inner cell-membrane). Phagocytic scavengers, such as macrophages, have specialized receptors that recognize PS and carry out their disposal job in an orderly manner without eliciting an inflammatory response. (See the Perspective "Eat me or die", by Savill et al., in Science, Vol. 302, p. 1516, Nov. 28, 2003, and the corresponding research articles on new work by Li et al., and Wang et al. in the same issue of Science.)

In the studies on mouse embryos lacking PS receptors ("PSR knockout mice") conducted by Li and colleagues, un-ingested cells undergoing apoptosis accumulated in the brain and lungs, leading to neonatal lethality. These studies show how critical is the role of PS receptor (PSR) in the development of complex organisms such as mammals.

Intrinsic and extrinsic inducers

Apoptotic messages from outside the cell (called extrinsic inducers) will be described in the next section, on biochemical execution of apoptosis.

Apoptotic messages from inside the cell (intrinsic inducers) are a response to stress, such as nutrient deprivation or DNA damage, as explained by Chiarugi and Moskowitz in their previously mentioned article on PARP-1.

Both extrinsic and intrinsic pathways have in common the activation of central effectors of apoptosis, a group of cysteine proteases called caspases, which carry out the cleaving of both structural and functional elements of the cell, resulting in the previously described morphological changes.

Biochemical execution

Caspases are normally suppressed by IAP (inhibitor of apoptosis) proteins (see "Controlling the Caspases", by Stephen W. Fesik and Yigong Shi, in Science, Vol. 294, No. 5546, p. 1477, November 16, 2001). When a cell receives an apoptotic stimulus, IAP activity is relieved after SMAC (Second Mitochondria-derived Activator of Caspases, or its mouse homolog, called DIABLO), a mitochondrial protein, is released into the cytosol. SMAC binds to IAPs, and in doing so "inhibits the inhibitors", effectively preventing them from arresting the apoptotic process.

But before we go on to a short description of how SMAC is released, lets take a look at two well-studied extrinsically induced apoptotic processes: the TNF and the Fas pathways. Keep in mind, however, that both activating and inhibiting factors are present at each step of these pathways.

Tumor necrosis factor (TNF), a 157 amino acid inter-cellular signaling molecule (cytokine) produced mainly by activated macrophages, and is the major extrinsic mediator of apoptosis. The cell membrane has two specialized receptors for TNF: TNF-R1 and TNF-R2. The binding of TNF to TNF-R1 has been shown to fire-off the pathway that leads to activating the caspases (see "TNF-R1 Signaling: A Beautiful Pathway", by Guoqing Chen and David V. Goeddel, in Science, Vol. 296, No. 5573, p. 1634).

Fas (a.k.a. Apo-1 or CD95), is another receptor of extrinsic apoptotic signals in the cell membrane, and belongs to the TNF receptor superfamily. (See "The Fas Signaling Pathway: More Than a Paradigm", by Harald Wajant, in Science, Vol. 296, No. 5573, p. 1635, May 31, 2002). The Fas ligand (FasL, the protein that binds to Fas and activates the Fas pathway) is a transmembrane protein, and is part of the TNF family. The interaction between Fas and FasL results in the formation of the death-inducing signaling complex (DISC), which contains the Fas-associated death domain protein (FADD) and caspases 8 and 10. In some types of cells (type I), processed caspase-8 directly activates other members of the caspase family, and triggers the execution of apoptosis; while in other types of cells (type II), the Fas DISC starts a feed-back loop that spirals into increasing release of pro-apoptotic factors from mitochondria (see bellow), and the amplified activation of caspase-8.

Downstream from TNF-R1 and Fas activation --at least in mammalian cells-- the proapoptotic molecules BAK and BAX are required in order to make the mitchondrial membrane permeable for the release of caspase activators. Just how BAX and BAK are controlled under the normal conditions of cells that are not undergoing apoptosis, is incompletely understood. But it has been found that a mitochondrial outer-membrane protein, VDAC2, interacts with BAK to keep this potentially lethal apoptotic effector under control. When the death signal is received, products of the activation cascade --such as tBID, BIM or BAD-- displace VDAC2: BAK and BAX are activated, and the mitochondrial outer-membrane becomes permeable. This results in the release of caspase activators, including cytochrome c (see "Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells", by Murphy, K.M., et al., in Nature Cell Death and Differentiation, Vol. 7, No. 1, Jan. 2000, p. 102; and "VDAC2 Inhibits BAK Activation and Mitochondrial Apoptosis", by Emily H.-Y. Cheng, Tatiana V. Sheiko, et al., in Science, Vol. 301, No. 5632, July 25, 2003, p. 513).

Release of citochrome c and SMAC from the mitochondrion result in the caspase-9 activating apoptosome, which in turn activates executioner caspase-3.

(The canonical Fas pathway is available in Science's Signal Transduction Knowledge Environment, at http://stke.sciencemag.org/cgi/cm/CMP_7966. The canonical TNF pathway is available at http://stke.sciencemag.org/cgi/cm/CMP_7107; but be aware that access to STKE's items is restricted to subscribers.)

The whole process requires energy and a cell machinery not too damaged. If the cell damage is between certain levels, the cell can start the earliest events of apoptosis and then continue with a necrosis.

Readers should be aware, however, that the apoptotic pathways that have been summarily described are subject to regulatory mechanisms, and that there is not a 1-to-1 relationship between the reception of TNF or FasL and the complete execution of an apoptotic pathway. Fas, for instance, has been implicated --in a seemingly ironic way-- in cell proliferation, through pathways that are not yet well understood (see the afore-quoted article by Wajant); and both Fas and TNF-R1 trigger events that activate the transcription factor nuclear factor kappa B, which induces the expression of genes that play an important role in diverse biological processes, including cell growth and death, development, and immune responses (see the afore-quoted paper by Chen and Goeddel).

The link between TNF and apoptosis shows why an abnormal production of TNF plays a fundamental role in several human diseases, especially (but not only) in autoimmune diseases, such as diabetes and multiple sclerosis.

Apoptosis and the role of interferon in tumor suppression

In their previously mentioned article on the "Integration of interferon-alpha/beta signaling to p53 responses...", Takaoka and co-worker describe their research on how interferon alpha and beta (IFN-alpha/beta)induce transcription of the p53 gene, resulting in the increase of p53 protein level and enhancement of cancer cell-apoptosis. p53 is a tumor suppressor, and is considered as a negative-growth and anti-oncogenic factor.

Work carried out by Takaoka and colleagues has contributed to clarify the role played by interferon in the treatment of some forms of human cancer, and has provided knowledge on the link between p53 and IFN alpha/beta. The p53 response not only contributes to tumor suppression, but is also important in eliciting an apoptotic response to viral infection and consequent damage to the cell's reproductive cycle.

Increasing evidence links cancer with defective apoptotic pathways

Liling Yang et al. reported in the Feb. 15, 2003, issue of Cancer Research the results of their work in the role played by a defective death signal in a type of lung cancer cells called NCI-H460 (human non-small cell lung cancer cells). They found that cross-linked inhibitor of apoptosis (XIAP) proteins are overexpressed in H460 cells. XIAPs bind to the processed form of caspase-9, and suppress the activity of apoptotic activator cytochrome c (the apoptosome produced by the mitochondrion).

The apoptotic pathway was found to be dramatically restored in H460 cells with a Smac peptide (SmacN7) that targets IAPs. Yang and her team successfully developed a SmacN7 peptide that selectively reversed apoptosis resistance --and, hence, tumor growth-- in H460 cells in mice.

Role of apoptotic products in tumor immunity

An interesting case of re-use and feed-back of apoptotic products was presented by Matthew L. Albert in a research article that won him an Amersham Biosciences & Science Prize for Young Scientists in Molecular Biology, and published in Science Online in December, 2001. Albert described how dendritic Cells, a type of antigen-presenting cells, phagocytose (that is, engulf) apoptotic tumor cells. Upon maturation, these dendritic cells present antigen (derived from the apoptotic corpses) to killer T cells, which are then primed for the eradication of cells undergoing malignant transformation. This apoptosis-dependent pathway for T cell activation is not present during necrosis, and has opened exciting posibilities in tumor immunity research.

Evolutionary origin of the apoptotic process

Biologists had long suspected that mitochondria originated from bacteria that had been incorporated as endosymbionts (that is, a living body "living together inside") of larger, eukaryotic cells. It was Lynn Margulis who, since 1967, began championing this theory, that has since been widely accepted (see "The Birth of Complex Cells", by Christian de Duve, Scientific American Vol. 274, 4, April, 1996). The most convincing evidence for this theory is the fact that mitochondria have their own DNA, and are equipped with their own genes and replication apparatus.

This evolutionary step must have been more than risky for the eukaryotes that began to engulf energy-producing prokaryotic bacteria, the ancestors of mitochondria. The drama is still enacted today in our own white blood cells (which, it must be said, are much better equipped to entrap and destroy bacteria that intend to invade our bodies). Most of the time, invading bacteria are destroyed by the white blood cells; but, oftentimes, the chemical warfare waged by the prokaryotes succeeds, with the known consequences of infection, and the resulting damage.

One of those rare events in evolution, about two billion years before the present, must have made it possible for certain eukaryotes and energy-producing prokaryotes not only to coexist, but to mutually benefit from their symbiosis.

In a very real and immediate sense, it can be said that eukaryotic cells live poised between life and death, because mitochondria still retain their repertoire of molecules that can trigger cell suicide (see the afore-quoted article by Chiarugi and Moskowitz, in Science 297, p. 200). Given certain signals or insults to cells—such as feed-back from neighbors, stress or DNA damage—mitochondria release caspase activators that produce the cell-death-inducing biochemical cascade.

As has been previously explained at the beginning of this article, however, this fine equilibrium between life and death that all of us eukaryotic beings carry most intimately and deeply, is essential to life.

See also: Immunology -- Biochemistry



In the News

Targeting cell pathway may prevent relapse of leukemia
About 40 percent of children and up to 70 percent of adults in remission from acute myelogenous leukemia (AML) will have a relapse. In recent years, doctors have come to believe that this is due to leukemia stem cells, endlessly replicating cancer cells that generate the immature blood cells characteristic of leukemia and are resistant to typical cancer treatments.

Famous Cases: Iva Toguri d’Aquino and "Tokyo Rose"
Background about Iva Toguri d'Aquino, who died in September 2006 and was most identified with "Tokyo Rose,"a "fabricated name given by soldiers to a series of American-speaking women who made propaganda broadcasts"in the South Pacific during World War II. Includes a description of her early life (she was born in Los Angeles and graduated from UCLA) and of her presidential pardon in 1977. From the Federal Bureau of Investigation (FBI).

Brain Size May Depend Upon How Neural Cells Are Cleaved
Howard Hughes Medical Institute researchers have discovered a novel way in which the brain size of developing mammals may be regulated. They have identified a signaling pathway that controls the orientation in which dividing neural progenitor cells are cleaved during development. The researchers speculate that this type of regulatory decision point may play a powerful role in determining the ultimate size of the mammalian brain.

Computer Program Helps Farmers Make Decisions About Pastureland
A team in Virginia Tech's College of Agriculture and Life Sciences is leading the development of the Pastureland Management System (PLMS), a free, practical, and portable computer-based aid program that helps livestock farmers compare different strategies for managing their land and livestock.

Flu mechanics
With the holiday season almost upon us, that means only one thing, flu is also on its way and if the scaremongers are to be believed the long-forewarned bird flu epidemic might follow in its wake any time soon.Now, US researchers have put to work the 15-ton 900 MHz NMR machine at Florida State U [...]

Could Fungal Collection Hold The Key To New Life-saving Drugs?
Scientists may be one step closer to finding new drugs to fight MRSA, cancers and other diseases, after CABI, a leading bioservices organisation announced that its fungal collection will be screened by the University of Strathclyde.

Poxvirus Used To Fight Cancer: Malignant Human Brain Tumors 'Cured' In
A cross-Canada scientific collaboration has successfully tested a potent new cancer-fighting virus that eliminates malignant brain tumors and prolongs survival in mice with a single injection. The scientists -- from Calgary and London, Ontario -- have shown for the first time that myxoma virus, a poxvirus, will kill human brain tumors in mice and prolong the animals' survival.

Women of Ravensbrück: Portraits of Courage
This exhibit looks at the history and background of the Ravensbrück camp, a World War II concentration camp for women. It features stories from several inmates, images of the camp and of prisoner art, and essays on topics such as children, medical experiments, spiritual resistance, and concentration camp cookbooks. Based on an exhibit at the Florida Holocaust Museum, this is part of virtual museum of the University of Minnesota Center of Holocaust and Genocide Studies.

When She's Turned On, Some Of Her Genes Turn Off, Fish Study Shows
When a female is attracted to a male, entire suites of genes in her brain turn on and off, show biologists from the University of Texas at Austin studying swordtail fish.

Some Don't Like It Hot: Unraveling The Molecular Basis Of Thermotaxis
The songwriter Noel Coward once declared that only mad dogs and Englishmen went out in the midday sun. Now MIT biologists have a third candidate--fruit flies with defects in a gene called dTrpA1.




MP3 Music Downloads

Preview songs, Download Free Music,Burn CDs at ITunes.com
iTunes_RGB_9mm

 


Google




InformationQuickFind.com - Find Information Fast

Links | Privacy Policy | News |